Substituted 4-phenyltetrahydroisoquinolinium salts, process for their preparation, their use as medicament, and medicament containing them
The invention relates to compounds of the formula I 
wherein
R1, R2, R3 and R4 are independently of one another H, F, Cl, Br, I, CN, NO2, OH, NH2, CaH2a+1, CqqH2qqxe2x88x921, OCbH2b+1, COOR50, OCOR50, COR50 or Oxxe2x80x94(CH2)yxe2x80x94 phenyl; wherein
a and b are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups CaH2a+1 and OCbH2b+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qqxe2x88x921 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R50 is H or CcH2c+1,
c is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CcH2c+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
x is zero or 1;
y is zero, 1, 2, 3 or 4, where the phenyl ring in the group Oxxe2x80x94(CH2)yxe2x80x94 phenyl is unsubstituted or substituted by 1-3 independently chosen from F, Cl, Br, CN, NO2, OH, NH2 and CdH2d+1,
d is 1, 2, 3 or 4, wherein the group CdH2d+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R1, R2, R3 and R4 are independently of one another chosen from a heteroaryl with at least one heteroatom chosen from 1, 2, 3 or 4 N atoms, 1 oxygen atom and 1 S atom, present as ring atoms; or
R1, R2, R3 and R4 are independently of one another CONR11R12 or NR11R12;
wherein
R11 and R12 are independently of one another H, CeH2e+1, or CrrH2rrxe2x88x921,
e is 1, 2, 3, 4, 5, 6, 7 or 8;
rr is 3, 4, 5, 6, 7, or 8, wherein the groups CeH2e+1 and CrrH2rrxe2x88x921 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR13;
R13 is H or CfH2f+1;
f is 1, 2, 3 or 4, wherein the group CfH2f+1 is unsubsitituted or substituted where one or
more H atoms are replaced by F atoms; or
R13 and a CH2 group of R11 or R12 together with the N atom to which they are bonded form a 5- or 6-membered ring; or
R11 and R12 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring; or
R11 and R12 are independently of one another COR14, CSR14 or SO2R14; wherein
R14 is CgH2g+1;
g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CgH2g+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms, and/or one or more CH2 groups are replaced by O or NR13; or
R1, R2, R3 and R4 are independently of one another xe2x80x94Ohxe2x80x94SOjxe2x80x94R15; wherein
h is zero or 1;
j is zero, 1 or 2;
R15 is CkH2k+1, OH, OClH2l+1 or NR17R18;
k is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CkH2k+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;
l is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group OClH2l+1 is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;
R17 and R18 are independently of one another H or CmH2m+1;
m is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CmH2m+1 is unsubstituted or substituted where one or more H atoms is replaced by F atoms and/or one or more CH2 groups are replaced by O, CO, CS or NR19; R19 is H or CnH2n+1;
n is 1, 2, 3 or 4, wherein the group CnH2n+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R17 and R18 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring; or
R19 and a CH2 group of R17 or R18 together with the N atom to which they are bonded form a 5- or 6-membered ring;
R5 and R6 are independently of one another CpH2p+1, CssH2ssxe2x88x921, COR20 or SO2R20; wherein
p is 1, 2, 3, 4, 5, 6, 7 or 8;
ss is 3, 4, 5, 6, 7 or 8;
R20 is CqH2q+1;
q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups CpH2p+1, CssH2ssxe2x88x921 and CqH2q+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR21;
R21 is H or CrH2r+1;
r is 1, 2, 3 or 4; wherein the group CrH2r+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R7 is H, F, Cl, Br, I, CsH2s+1, CddH2ddxe2x88x921, OH, OCtH2t+1 or OCOR22; wherein s and t are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8;
dd is 3, 4, 5, 6, 7 or 8, wherein the groups CsH2s+1, CddH2ddxe2x88x921 and OCtH2t+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R22 is CuH2u+1;
u 1, 2, 3 or 4, wherein the group CuH2u+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R8, R9 and R10 are independently of one another xe2x80x94Ovxe2x80x94SOwxe2x80x94R23; wherein
v is zero or 1;
w is zero, 1 or 2;
R23 is CnnH2nn+1, CmmH2mmxe2x88x921, OH, OCppH2pp+1 or NR25R26; nn and pp are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, mm is 3, 4, 5, 6, 7 or 8, wherein the groups CnnH2nn+1, CmmH2mmxe2x88x921 and OCppH2pp+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R25 and R26 are independently of one another H, CN, CzH2z+1, or CzzH2zzxe2x88x921;
z is 1, 2, 3, 4, 5, 6, 7 or 8;
zz is 3, 4, 5, 6, 7 or 8, wherein the group CzH2z+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms and,
wherein the group CzH2z+1, is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O, CO, CS or NR27;
R27 is H or CaaH2aa+1;
aa is 1, 2, 3 or 4, wherein the group CaaH2aa+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded form a 5- or 6-membered ring; or
R25 and R26 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring, or
R8, R9 and R10 are independently of one another NR32COR30, NR32CSR30 or NR32SObbR30; wherein
R30 is H, CccH2cc+1, CyyH2yyxe2x88x921, pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH2 group is replaced by O or NR33;
R32 and R33 are independently of one another H or ChH2h+1;
bb is 2 or 3;
cc is 1, 2, 3, 4, 5, 6, 7 or 8;
yy is 3, 4, 5, 6, 7 or 8;
h is 1, 2, 3, 4, 5, 6, 7 or 8,
wherein the group ChH2h+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms, and wherein the groups CccH2cc+1 and CyyH2yyxe2x88x921 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR31;
R31 is H, CkkH2kk+1, or COR65;
kk is 1, 2, 3, or 4; wherein the group CkkH2kk+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms, R65 is H, or CxxH2xx+1;
xx is 1, 2, 3 or 4, wherein the group CxxH2xx+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R31 together with a CH2 group of R30 and the N atom to which they are jointly bonded forms a 5-, 6- or 7-membered ring; or
R30 is a 5- or 6-membered heteroaryl with at least one hetero atom chosen from 1, 2, 3 or 4 N atoms, 1 S atoms and 1 O atoms which is unsubstituted or substituted by up to three substituents chosen from F, Cl, Br, I, CooH2oo+1, and NR70R71;
R70 and R71 are independently of one another H, CuuH2uu+1 or COR72;
R72 is H, or CvvH2vv+1;
oo, uu and vv are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups CooH2oo+1, CuuH2uu+1 and CvvH2vv+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R8, R9 and R10 are independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1, CwwH2wwxe2x88x921, OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 OCOR42;
ee and ff are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8;
ww is 3, 4, 5, 6, 7 or 8, wherein the groups CeeH2ee+1, CwwH2wwxe2x88x921 and OCffH2ff+1 independently of one another are unsubstituted or substituted
where one or more H atoms are replaced by F atoms;
R40 and R41 are independently of one another H or CttH2tt+1;
tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CttH2tt+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or where one or more CH2 groups are replaced by O or NR44;
R44 is H or CggH2gg+1;
gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CggH2gg+1 is unnsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R40 and R41 with the N atom to which they are bonded for a 5- or 6-membered ring;
R42 is H or ChhH2hh+1;
hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group ChhH2hh+1 is unnsubstituted or substituted where one or more H atoms are replaced by F atoms;
Y is chosen from fluorine, chlorine, bromine, iodine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids and sulfonic acids;
and their pharmaceutically acceptable salts, and the trifluoroacetic acid salts.
In another embodiment, compounds of the formula 1 are chosen from:
R1, R2, R3 and R4 are independently of one another, H, F, Cl, Br, I, CN, NO2, OH,
NH2, CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, OCbH2b+1, or COOR50; wherein a and b are independently of one another 1, 2, 3 or 4, wherein the group CaH2a+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R50 is H or CcH2c+1;
c is 1, 2, 3 or 4, wherein the group CcH2c+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
or R1, R2, R3 and R4 are independently of one another a 5- or 6-membered heteroaryl chosen from imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl; or
R1, R2, R3 and R4 are independently of one another CONR11R12 or NR11R12; wherein
R11 and R12 are independently of one another H, CeH2e+1, or CrrH2rrxe2x88x921;
e is 1, 2, 3 or 4;
rr is 3, 4, 5 or 6, wherein the groups CeH2e+1 and CrrH2rrxe2x88x921 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R11 and R12 independently of one another are hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or
R11 and R12 together with the N atom to which they are bonded form a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring; or
R11 and R12 are independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO2R14; wherein
R14 is CgH2g+1;
g is 1, 2, 3 or 4, wherein the group CgH2g+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R1, R2, R3 and R4 are independently of one another OSO3H, SO3H, SO2R15; wherein
R15 is CkH2k+1, OClH2l+1 or NR17R18;
k 1, 2, 3 or 4, wherein the group CkH2k+1 is unsubstituted or substituted where one ore more H atoms are replaced by F atoms;
l 1, 2, 3 or 4, wherein the group OClH2l+1 is unsubstituted or substituted where one ore more H atoms are replaced by F atoms;
R17 and R18 are independently of one another H, CmH2m+1 or CmH2m+1, in which a first CH2 group bonded to the nitrogen of NR17R18 is replaced by CO and a second CH2 group is replaced by NR19;
m 1, 2, 3, 4 or 5, wherein the group CmH2m+1 is unsubstituted or substituted where one or more H atoms is replaced by F atoms;
R19 is H or CnH2n+1;
n is 1, 2, 3 or 4, wherein the group CnH2n+1 is unsubstituted or substituted where one or more H atoms is replaced by F atoms; or
R17 and R18 together with the N atom to which they are bonded a 5- or 6-membered ring;
R5 and R6 are independently of one another CpH2p+1;
p is 1, 2, 3 or 4, wherein the group CpH2p+1 is unsubstituted or substituted where one or more H atoms is replaced by F atoms;
R7 is H, CsH2s+1, OCtH2t+1 or OCOR22; wherein s and t are independently of one another 1, 2, 3 or 4, wherein the groups CsH2s+1 and OCtH2t+1 independently of another are unsubstituted or substituted where one or more H atoms is replaced by F atoms;
R22 is CuH2u+1;
u is 1, 2, 3 or 4; wherein the group CuH2u+1 is unsubstituted
or substituted where one or more H atoms is replaced by F atoms;
R8, R9 and R10 are independently of one another OSO3H, SO3H or SO2R23; wherein
R23 is CnnH2nn+1, CmmH2mmxe2x88x921, OCppH2pp+1 or NR25R26;
nn and pp are independently of one another 1, 2, 3, 4 or 5,
mm is 3, 4, 5 or 6, wherein the groups CnnH2nn+1, CmmH2mmxe2x88x921 and OCppH2pp+1 independently of another are unsubstituted or substituted where one or more H atoms is replaced by F atoms;
R25 and R26 are independently of one another H, CN, CzH2z+1 or CzH2z+1, in which a first CH2 group bonded to the nitrogen of NR25R26 is replaced by CO or CS and a second CH2 is replaced by NR27;
z is 1, 2, 3, 4, 5 or 6; wherein the group CzH2z+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R27 is H or CaaH2aa+1;
aa is 1, 2, 3 or 4, wherein the group CaaH2aa+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded form a 5- or 6-membered ring; or
R25 and R26 together with the N atom to which they are bonded form a 5- or 6-membered ring; or
R8, R9 and R10 are independently of one another NR32COR30, NR32CSR30 or NR32SO2R30; wherein
R30H, OH, CccH2cc+1, CyyH2yyxe2x88x921, pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH2 group is replaced by O or NR33;
R32 and R33 are independently of one another H or ChH2h+1;
cc is 1, 2, 3, 4, 5 or 6;
yy is 3, 4, 5 or 6;
h is 1, 2, 3 or 4; wherein the group ChH2h+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms, and wherein the groups CccH2cc+1 and CyyH2yyxe2x88x921 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR31;
R31 is H, CkkH2kk+1 or COR65;
kk is 1, 2, 3, or 4, wherein the group CkkH2kk+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms,
R65 is H or CxxH2xx+1;
xx is 1, 2, 3 or 4, wherein the group CxxH2xx+1 is unsubstituted where one or more H atoms are replaced by F atoms; or
R31 together with a CH2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or
R30 is a 5- or 6-membered heteroaryl chosen from pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl and oxazolyl;
which is unsubstituted or substituted by up to three substituents chosen from F, Cl, Br, I, CooH2oo+1, and NR70R71,
R70 and R71 are independently of one another H, CuuH2uu+1 or COR72;
R72 is H or CvvH2vv+1;
oo, uu and vv are independently of one another 1, 2, 3 or 4, wherein the groups CooH2oo+1, CuuH2uu+1 and CvvH2vv+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R8, R9 and R10 are independently of one another H, F, Cl, Br, I, NO2, CN, OH, NH2, CeeH2ee+1, CwwH2wwxe2x88x921, OCffH2ff+1, NR40R41, CONR40R41, COOR42, COR42 or OCOR42;
ee and ff are independently of one another 1, 2, 3 or 4;
ww is 3, 4, 5 or 6, wherein the groups CeeH2ee+1, CwwH2wwxe2x88x921 and OCffH2ff+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R40 and R41 are independently of one another H or CttH2tt+1;
tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CttH2tt+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R40 and R41 are independently of one another chosen from hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl and piperidinoethyl; or
R40 and R41 together with the N atom to which they are bonded form a ring chosen from pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine;
R42 is H or ChhH2hh+1;
hh is 1, 2, 3 or 4, wherein the group ChhH2hh+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
Y is choen from fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids or sulfonic acids; and the pharmaceutically acceptable salts and trifluoroacetates thereof.
In another embodiment, compounds of the formula 1 are chosen from:
R1, R2, R3 and R4 are independently of one another H, F, Cl, Br, OH, NH2, CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, or OCbH2b+1;
a and b are independently of one another 1, 2, 3 or 4, wherein the groups CaH2a+1 and OCbH2b+1 independenly of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R1, R2, R3 and R4 are independently of one another NR11R12;
R11 and R12 are independently of one another H, CeH2e+1, or CrrH2rrxe2x88x921;
e is 1, 2, 3 or 4;
rr is 3, 4, 5 or 6, wherein the groups CeH2e+1 and CrrH2rrxe2x88x921 independently of one another are unsubtituted or substituted where one or more H atoms are replaced by F atoms; or
R11 and R12 together with the N atom to which they are bonded form a ring chosen from pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or
R11 and R12 are independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO2R14; wherein
R14 is CgH2g+1;
g is 1, 2, 3 or 4, wherein the group CgH2g+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R1, R2, R3 and R4 are independently of one another OSO3H, SO3H, or SO2R15;
R15 is CkH2k+1 or NR17R18;
k is 1, 2, 3 or 4, wherein the group CkH2k+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R17 and R18 are independently of one another H or CmH2m+1;
m is 1, 2, 3, 4 or 5, wherein the group CmH2m+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R17 and R18 together with the N atom to which they are bonded form a 5- or 6-membered ring;
R5 and R6 are independently of one another methyl or trifluoromethyl;
R7 is H;
R8, R9 and R10 are independently of one another OSO3H, SO3H or SO2R23; wherein
R23 is CnnH2nn+1 or NR25R26;
nn is 1, 2, 3, 4 or 5, wherein the group CnnH2nn+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
R25 and R26 are independently of one another H, CN, CzH2z+1, or CzH2z+1 in which a first CH2 group bonded to the nitrogen of NR25R26 is replaced by CO or CS and a second CH2 is replaced by NR27;
z is 1, 2, 3, 4, 5 or 6, wherein the group CzH2z+1 is unsubstituted or substituted where one ore more H atoms are replaced by F atoms;
R27 is H or CaaH2aa+1;
aa is 1, 2, 3 or 4, wherein the group CaaH2aa+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded a 5- or 6-membered ring; or
R25 and R26 together with the N atom to which they are bonded form a 5- or 6-membered ring, or
R8, R9 and R10 are independently of one another NR32COR30, NR32CSR30 or NR32SO2R30; wherein
R30 is H, OH, CccH2cc+1, CyyH2yyxe2x88x921, pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH2 group is replaced by O or NR33;
R32 and R33 are H, methyl or CF3;
cc is 1, 2, 3, 4, 5 or 6;
yy is 3, 4, 5 or 6, wherein the groups CccH2cc+1 and CyyH2yyxe2x88x921 independently of one another are unsubstituted or substituted where one ore more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR31;
R31 is H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl; or
R31 together with a CH2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or
R30 is pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by up to 3 substituents chosen from F, Cl, methyl, ethyl, trifluoromethyl, NH2, and NHacetyl; or
R8, R9 and R10 are independently of one another H, F, Cl, OH, NH2, CeeH2ee+1, CwwH2wwxe2x88x921, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42,
ee and ff are independently of one another 1, 2, 3 or 4;
ww is 3, 4, 5 or 6, wherein the groups CeeH2ee+1, CwwH2wwxe2x88x921 and OCffH2ff+1 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms; R40 and R41 are H or CttH2tt+1;
tt is 1, 2, 3 or 4, wherein the group CttH2tt+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms; or
R40 and R41 independently of one another are hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or
R40 and R41 together with the N atom to which they are bonded form a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring;
R42 is H or ChhH2hh+1;
hh is 1, 2, 3 or 4, wherein the ChhH2hh+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;
Y is chosen from fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids and sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
In another embodiment, compounds of the formula 1 are chosen from
R1 and R3 is H;
R2 and R4 are independently of one another H, F, Cl, Br, OH, NH2, CaH2a+1, cycloalkyl with 3, 4, 5 or 6 C atoms, or OCbH2b+1; wherein
a and b are independently of one another 1, 2, 3 or 4, wherein the groups CaH2a+1 and OCbH2b+1 independently of one another are unsubstituted or substituted where one or more H atoms to be replaced by F atoms;
or R2 and R4 are independently of one another NR11R12; wherein
R11 and R12 are independently of one another H or CeH2e+1,
e is 1, 2, 3 or 4, wherein the group CeH2e+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms; or
R11 and R12 together with the N atom to which they are bonded form a ring chosen from pyrrolidine, piperidine, N-methylpiperazine, piperazine and morpholine; or
R11 and R12 are independently of one another COR14, CSR14, CONHR14, CSNHR14 or SO2R14;
R14 is CgH2g+1;
g is 1, 2, 3 or 4, wherein the group CgH2g+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms; or
R2 and R4 are independently of one another OSO3H, SO3H, or SO2R15; wherein
R15 is CkH2k+1 or NR17R18;
k is 1, 2, 3 or 4, wherein the group CkH2k+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms;
R17 and R18 are independently of one another H or CmH2m+1;
m is 1, 2, 3, 4 or 5, wherein the group CmH2m+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms; or
R17 and R18 together with the N atom to which they are bonded form a 5- or 6-membered ring;
R5 and R6 are independently of one another methyl or trifluoromethyl;
R7 is H;
R8, R9 and R10 are independently of one another OSO3H, SO3H or SO2R23; wherein
R23 is CnnH2nn+1 or NR25R26;
nn is 1, 2, 3, 4 or 5, wherein the group CnnH2nn+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms;
R25 and R26 are independently of one another H, CN, CzH2z+1, or CzH2z+1 in which a first CH2 group bonded to the nitrogen of NR25R26 is replaced by CO or CS and a second CH2 is replaced by NR27;
z is 1, 2, 3, 4, 5 or 6, wherein the group CzH2z+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms;
R27 is H or CaaH2aa+1;
aa is 1, 2, 3 or 4, wherein the group CaaH2aa+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms or
R27 and a CH2 group of R25 or R26 together with the N atom to which they are bonded form a 5- or 6-membered ring; or
R25 and R26 together with the N atom to which they are bonded form a 5- or 6-membered ring, or
R8, R9 and R10 are independently of one another NR32COR30, NR32CSR30 or NR32SO2R30;
R30 is H, OH, CccH2cc+1, CyyH2yyxe2x88x921, pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH2 group is replaced by O or NR33;
R32 and R33 are independently of one another H, methyl or CF3;
cc is 1, 2, 3, 4, 5 or 6;
yy is 3, 4, 5 or 6, wherein the groups CccH2cc+1 and CyyH2yyxe2x88x921 independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH2 groups are replaced by O or NR31;
R31 is H, methyl, ethyl, CF3, CH2CF3, acetyl or propionyl; or
R31 together with a CH2 group of R30 and the N atom to which they are jointly bonded form a 5- or 6-membered ring; or
R30 is pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted or substituted by up to 3 substituents chosen from F, Cl, methyl, ethyl, trifluoromethyl, NH2, and NHacetyl; or
R8, R9 and R10 are independently of one another H, F, Cl, OH, NH2, CeeH2ee+1, CwwH2wwxe2x88x921, OCffH2ff+1, NR40R41, CONR40R41, COOR42 or OCOR42,
ee and ff are independently of one another 1, 2, 3 or 4;
ww is 3, 4, 5 or 6, wherein the groups CeeH2ee+1, CwwH2wwxe2x88x921 and OCffH2ff+1 independently of one another are unsubstituted or substituted where one or more H atoms to be replaced by F atoms;
R40 and R41 is H or CttH2tt+1;
tt is 1, 2, 3 or 4, wherein the group CttH2tt+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms; or
R40 and R41 are independently of one another hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl or piperidinoethyl; or
R40 and R41 together with the N atom to which they are bonded form a pyrrolidine, piperidine, N-methylpiperazine, piperazine or morpholine ring;
R42 is H or ChhH2hh+1;
hh is 1, 2, 3 or 4, wherein the group ChhH2hh+1 is unsubstituted or substituted where one or more H atoms to be replaced by F atoms;
Y is chosen from fluorine, chlorine, bromine, hydroxyl and all anionic forms of pharmacologically acceptable mono-, di- or tricarboxylic acids and sulfonic acids;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
In another embodiment, compounds of the invention are chosen from the following tetrahydroisoquinolinium salts:
a. 6,8-dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate;
b. 6,8-dichloro-2,2-dimethyl-4-(4-sulfamoylphenyl)-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate;
c. 4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide;
d. (+)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide;
e. (xe2x88x92)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide;
f. (+)-4-(4-acetylaminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride;
g. 4-(4-aminophenyl)-6,8-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride; hydrochloride;
h. 6,8-dichloro-4-[4-(3-ethylureido)phenyl]-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium chloride;
and the pharmaceutically acceptable salts thereof.
The defined alkyl radicals and partly or completely fluorinated alkyl radicals may be both straight-chain and branched. Groups CCaH2axe2x88x921 and their analogs as far as CyyH2yyxe2x88x921 mean either the corresponding alkenyls, cycloalkyls, cycloalkylalkyls or alkylcycloalkyl.
Heteroaryls of the invention, include, for example. 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3-or 5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. The corresponding N-oxides of these compounds may additionally be encompassed, that is to say, for example, 1-oxy-2-, 3- or 4-pyridyl.
Of these, in one embodiment, the 5- or 6-membered heterocycles are chosen. Examples of heterocycles include imidazolyl, pyrazolyl, pyridyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl.
Suitable pharmacologically acceptable anions Y are, for example, those of the following mono-, di- or tricarboxylic acids or sulfonic acids: acetic acid, adipic acid, citric acid, succinic acid, malic acid, fumaric acid, gluconic acid, glutamic acid, glycerolphosphoric acid, HCl, HBr, lactic acid, malonic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, nitric acid, di(2-hydroxy-3-carboxynaphth-1-yl)methane (pamoates), phosphoric acid, sulfuric acid, tartaric acid, toluenesulfonic acid.
In the case of multiply negatively charged acid anions, Y, it is possible for one or more cations according to the invention to be present.
If the compounds of the formula I contain one or more centers of asymmetry, these may have both the S and the R configuration. The compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof.
The terminal CH3 groups in an alkyl chain are also regarded as CH2 units and, in this connection, are understood as CH2xe2x80x94H groups.
In one embodiment, suitable pharmacologically and physiologically or toxicologically acceptable salts of the compounds of the formula I are: the alkali metal salts, such as sodium or potassium salts, or the alkaline earth metal salts, e.g. calcium or magnesium salts, or the ammonium salts, e.g. salts with ammonia or organic amines or amino acids. Compounds of the formula I which have one or more basic, i.e. protonatable, groups, or contain one or more basic heterocyclic rings, may also be used in the form of their physiologically acceptable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates etc.
The salts of the following acids are, for example, also suitable in the practice of the invention: maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid.
The published specifications WO 01 32 624 and WO 01 32 625 describe aryl substituted tetrahydroisoquinolines, which are not quaternary compounds, as inhibitors of reuptake of norepinephrine, dopamine and serotonin. Tetrahydroisoquinolines, also not as quaternary compounds, are described in the published specification EP 11 13 007 as estrogen agonists and antagonists, while German patent application 101 59 714.2 (DEAV2001/0072) proposes the use of 4-phenyltetrahydroisoquinolines as NHE inhibitors. Methods for preparing the compounds used are also described. The synthesis of tetrahydroisoquinolines II has been described in the German patent application 101 59 714.2 (DEAV2001/0072):
Thus, in one embodiment, the compounds according to the invention can be prepared starting from the benzylamine precursors IV. These in turn may, if not obtainable commercially, be synthesized by standard processes from the corresponding benzyl chlorides or benzyl bromides III. 
The benzylamines IV obtained in this way are alkylated in a manner known to the skilled worker with the appropriately substituted alpha-bromoacetophenone compounds V. 
The alpha-bromacetophenone compounds V may be obtained, for example, from the corresponding acetophenone precursors by bromination in processes known from the literature. The desired tetrahydroisoquinolines II may be obtained by known processes by reduction of the carbonyl group in VI and subsequent acid-catalyzed cyclization of the corresponding alcohols VII (cf. Tetrahedron Lett.; 1989, 30, 5837; Org. Prep. Proced. Int.; 1995, 27, 513; J. Med. Chem.; 1973,16, 342). 
When R7 is not equal to H, the desired compounds of the formula II can be prepared for example from the iodides VIII by halogen/metal exchange and subsequent nucleophilic attack of the intermediate organolithium species on the carbonyl group (cf. Chem. Pharm. Bull.; 1995, 43, 1543). 
The tertiary alcohols II synthesized in this way may be converted by known methods into other derivatives.
Alkyl-branched analogs (II) may be prepared by alkylating the corresponding diphenylacetic esters X in the alpha position by known methods. The desired product XI may be converted by standard processes into the corresponding amides XII, which may be converted into the desired tetrahydroisoquinolines II in a Pictet-Spengler-analogous reaction (cf. Tetrahedron; 1987, 43, 439; Chem. Pharm. Bull.; 1985, 33, 340). 
In another embodiment, the compounds of the invention can be prepared in a manner known to the skilled worker by alkylation reactions starting from II. 
Examples of alkylating reagents which can be used are the appropriate halides, methanesulfonates, trifluoromethanesulfonates or else tosylates. The tetrahydroisoquinolinium salts produced in the reaction may easily be converted into other salts by ion exchange chromatography in a known manner.
As used herein, treating or treatment includes the treating of, for example, a patient inflicted with a disease or condition, as well as the prevention, prophylaxis, or protective treatment of a patient. Treatment also includes treating a subject susceptible to or predisposed to developing a disease or condition, which could include patients in whom a disease or condition has not yet presented as well as patients in whom the disease has been successfully treated but could redevelop or reoccur.
In one embodiment, compounds of the formula I may be excellent inhibitors of the sodium-hydrogen exchanger (NHE)xe2x80x94especially of the sodium-hydrogen exchanger of subtype 3 (NHE3).
On the basis of these properties, the compounds of the invention may be suitable for the treatment of disorders caused by oxygen deficiency. The compounds may be, as a result of their pharmacological properties, outstandingly suitable as antiarrhythmic medicaments with a cardioprotective component for prophylaxis of infarction and for treatment of infarction, and for the treatment of angina pectoris, in which connection they also inhibit or greatly reduce in a preventive manner the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the induction of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I which are used according to the invention may, as a result of inhibition of the cellular Na+/H+ exchange mechanism, be used as medicaments for the treatment of all acute or chronic damage induced by ischemia or disorders induced primarily or secondarily thereby. This relates to the use thereof as medicaments for surgical interventions, e.g. in organ transplantations, in which cases the compounds can be used both to protect the organs in the donor before and during removal, to protect removed organs for example on treatment with or storage thereof in physiological bath fluids, as well as during the transfer into the recipient organism. The compounds may likewise be valuable medicaments with a protective action during the performance of angioplastic surgical interventions, for example on the heart as well as peripheral vessels. In accordance with their protective action against ischemia-induced damage, the compounds may also be suitable as medicaments for the treatment of ischemias of the nervous system, especially of the CNS, in which connection they may be suitable for example for the treatment of stroke or of cerebral edema. In addition, the compounds of the formula I which are used according to the invention may likewise be suitable for the treatment of types of shock, such as, for example, of allergic, cardiogenic, hypoglycemic and bacterial shock.
In addition, the compounds of the invention may induce an improvement in the respiratory drive and may therefore be used to treat respiratory conditions associated with the following clinical conditions and diseases: disturbance of central respiratory drive (e.g. central sleep apnea, sudden infant death, postoperative hypoxia), muscle-related breathing disorders, breathing disorders after long-term ventilation, breathing disorders associated with altitude adaptation, obstructive and mixed type of sleep apnea, acute and chronic pulmonary disorders with hypoxia and hypercapnia. The compounds additionally may increase the tone of the muscles of the upper airways, so that snoring is suppressed.
A combination of an NHE inhibitor with a carbonic anhydrase inhibitor (e.g. acetazolamide), the latter inducing metabolic acidosis and thus itself increasing respiratory activity, may provide an enhanced effect and reduced use of active ingredient.
In one embodiment, the compounds used according to the invention may have a mild laxative effect and accordingly may be used advantageously as laxatives or if there is a risk of constipation, in which case the prevention of the ischemic damage associated with constipation in the intestinal region may be provided.
In another embodiment the compounds used according to the invention may prevent the formation of gall stones.
In one embodiment, the compounds of the invention are furthermore may provide a strong inhibitory effect on the proliferation of cells, for example of fibroblast cell proliferation and the proliferation of smooth muscular muscle cells. The compounds may therefore be suitable as valuable therapeutic agents for diseases in which cell proliferation represents a primary or secondary cause, and therefore may be used as antiatherosclerotic agents, agents to prevent late complications of diabetes, cancers, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies and hyperplasias, in particular for prostate hyperplasia or prostate hypertrophy.
The compounds used according to the invention may also be effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger) which is elevated in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), also in those cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds used according to the invention may therefore be suitable as excellent and simple scientific tools, for example in their use as diagnostic agents for determining and distinguishing different types of hypertension, but also of atherosclerosis, of diabetes, proliferative disorders etc. The compounds of the invention may moreover be suitable for preventive therapy to prevent the development of high blood pressure, for example of essential hypertension.
It has additionally been found that NHE inhibitors may show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood lipid levels which are too high, so-called hyperlipoproteinemias, represent a considerable risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum lipoproteins therefore may have exceptional importance for the prophylaxis and regression of atherosclerotic lesions. The compounds used according to the invention may therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor. With this protection of the vessels against the syndrome of endothelial dysfunction, compounds of the invention may be valuable medicaments for the prevention and treatment of coronary vasospasms, of atherogenesis and of atherosclerosis, of left-ventricular hypertrophy and of dilated cardiomyopathy, and thrombotic disorders.
Compounds of the invention may also be used for: a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; a medicament for the prevention and treatment of snoring; a medicament for lowering blood pressure; a medicament for the prevention and treatment of disorders induced by ischemia and reperfusion of central and peripheral organs, such as acute renal failure, stroke, endogenous states of shock, intestinal disorders etc.; a medicament for the treatment of late damage from diabetes and chronic renal disorders, in particular of all inflammations of the kidneys (nephritides) which are associated with increased protein/albumin excretion; for producing a medicament for the treatment of infection by ectoparasites in human and veterinary medicine; for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably with angiotensin converting enzyme (ACE) inhibitors, with diuretics and saluretics such as furosemide, hydrochlorothiazide, pseudoaldosterone antagonists and aldosterone antagonists; with adenosine receptor modulators, in particular with adenosine receptor activators (A2 agonists), and with angiotensin receptor antagonists.
In one embodiment the compounds of the invention may be sodium-proton exchange inhibitors and may be administered as novel medicaments for lowering elevated blood lipid levels, and the combination of sodium-proton exchange inhibitors with hypotensive medicaments and/or medicaments with hypolipidemic activity is envisioned.
Medicaments which comprise a compound of the invention may, for example, be administered orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred administration being dependent on the particular characteristics of the disorder. The compounds I may moreover be used alone or together with pharmaceutical excipients, both in veterinary medicine and in human medicine.
The excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients, and other active ingredient carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or colors.
For a form for oral administration, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. It is moreover possible for the preparation to take place both as dry granules and as wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds used may be converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents.
The formulation may, if required, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. In one embodiment, such a preparation normally contains the active ingredient in a concentration of about 0.1 to 10, in particular of about 0.3 to 3, % by weight.
The dosage of the active ingredient of the compounds of the invention to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the disorder to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
In one embodiment, on average, the daily dose of a compound of the invention for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 10 mg/kg, preferably 1 mg/kg, of body weight. For acute episodes of the disorder, for example immediately after suffering a myocardial infarction, higher and, in particular, more frequent dosages may also be necessary, e.g. up to 4 single doses a day. Up to 200 mg a day may be necessary, in particular on i.v. administration, for example for a patient with infarction in the intensive care unit.
Descriptions of experiments and examples:
List of abbreviations used:
General
The retention times (Rt) indicated below relate to LCMS measurements with the following parameters:
The retention times relate to the MS spectra